Preparations containing the TIAB silver complex as an effective method of healing wounds and bacterial and viral infections:
20200408AD
infections, wound healing, silver, wound healing, silver compounds, antibiotic resistance, viral infections, TIAB:
Preparations containing the TIAB silver complex as an effective method of healing wounds and infections
In recent years, the problem of bacterial, fungal and viral infections has become an extremely important challenge for modern medicine. Insufficient efficacy of the antimicrobial substances used so far is being found more and more often, which leads to frequent recurrences of infections and serious complications. This is largely associated with the growing resistance of microorganisms to commonly used antimicrobial substances. One of the factors that leads to this condition is too frequent and sometimes unfounded use of antibiotics (e.g. in the course of a viral infection). The use of incorrectly selected substances (p / bacterial or p / fungal) or administration in too low doses also contributes to the development of resistance. The duration of therapy is also extremely important, because using the drug too shortly causes incomplete elimination of microorganisms and selection of resistant strains, which is the main reason for recurrence of infection [1].



One of the most serious medical problems are in-hospital infections. Among the pathogens responsible for nosocomial infections, a very high percentage of multi-drug resistant bacteria (so-called alarm pathogens) is found, among others: Klebsiella pneumoniae, Staphylococcus aureus or Acinetobacter baumanii, which may be difficult and long-lasting to eliminate. The most susceptible to infections are patients with disorders of the immune system (e.g. during immunosuppressive treatment) and people with associated diseases such as diabetes or chronic renal failure. The most common infections found in the hospital environment include urinary tract, lung, skin and subcutaneous infections. Therefore, in recent years, more and more attention has been paid to the prophylactic use of antimicrobial substances, thanks to which it is possible to reduce the risk of infection and sometimes serious clinical consequences of infection [2].





Antibacterial, antifungal and antiviral activity of silver compounds

Silver compounds have been widely used in medicine for years because of their strong antimicrobial properties. They occur in the form of metallic, ionic, salt complexes and nanoparticles. Currently on the market there is a wide range of products containing silver compounds that are widely used in such areas as dermatology, gynecology and ophthalmology. Silver nitrate was one of the first compounds to be used in medicine. It is still used today in the form of eye drops, which are commonly used in newborns to prevent infection of the Neisseria gonorrhoeae of the anterior segment (Credi procedure). However, currently silver compounds are most often used in the treatment of difficult to heal wounds, burns or pressure sores. A variety of topical preparations for external use are available, e.g. creams, gels or specialized active dressings. They contain silver in various forms, including: sulfodiazine, metallic silver, nanocrystalline, ionic, sulfate and colloidal silver. They enable treatment of chronic wounds covered by the infection process, and thus accelerate the healing process. Active dressings release Ag + ions as a result of contact with the secretions contained on the wound surface [3].

The mechanism of action of silver ions is complex. Silver ions inhibit many important metabolic processes in a bacterial cell. In addition, they disrupt ion transport in the cell, limit cell division, damage the cell membrane and DNA of microorganisms, causing denaturation and preventing them from multiplying in tissues. Active silver also disrupts the function of oxidative enzymes that are part of the electron transport chain, which results in increased production of free radicals that damage the proteins and DNA of the bacterial cell. Active silver ions also cause impairment of ribosome function [3]. It has also been shown that silver nanoparticles can disrupt the common communication system in bacteria, which is based on the ability to sense cell numbers called quorum sensing (QS). It is particularly important in the communication of bacteria living in the form of a biofilm [4].
The multidirectional effect of silver on a bacterial cell limits the development of resistance to this molecule. The spectrum of silver action is wide. Silver compounds, used as a topical antiseptic, have been shown to be effective against microorganisms such as: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Neisseria gonorrococci, Stococcus faecidis, Gardocene agalactiae (β-hemolytic streptococcus from influenza B), Candida albicans and Candida glabrata. In addition, the spectrum of silver action also includes pathogens characterized by high antibiotic resistance, including staphylococci (MRSA) and vancomycin resistant enterococci (VRE). Therefore, silver compounds are used to treat most chronic wounds. The effectiveness of silver is directly proportional to the concentration of active ions of this element (Ag +). However, due to the action of light, temperature, inorganic and organic compounds, Ag + ionic silver quickly loses its antimicrobial properties, returning to its metallic form. Inactive silver accumulates in the tissues, causing their damage, and thus may adversely affect the healing process. Therefore, in recent years, the focus has been on developing new forms of Ag + silver ions that are characterized by higher antimicrobial activity, while allowing for increased safety of use. One such form is the TIAB (titanium – argentum – benzoicum) form [5].

TIAB is a titanium dioxide molecule on which active nanoparticles of Ag + silver ions have been deposited in combination with benzalkonium chloride, which has resulted in increased antimicrobial activity. In addition, this form is characterized by increased durability compared to previously used antiseptics based on silver compounds. The covalent connection with the titanium molecule prevents the active Ag + form from changing to the non-ionic Ag0 form and accumulating silver in the tissues. It is also worth emphasizing that the TIAB complex includes silver in the form of nanoparticles with a size of 7 to 45 nm, which allows for intensive penetration of ions into the microbial cell. The particle diameter of the TIAB complex, determined by flow cytometry, is above 150 nm, this ensures the surface effect of the complex without the possibility of penetration into tissues and the bloodstream, but it still correlates with the dimensions of the smallest structures of pathogens, which include viruses. This allowed for obtaining high antimicrobial activity, because the TIAB complex can be used even at a 30-fold lower dose than is necessary in other antiseptic preparations containing silver compounds, while maintaining the same effectiveness [6].

The antibacterial properties of silver are widely known, but it is worth noting that the spectrum of the TIAB silver complex also covers other microorganisms. This compound is also characterized by high activity against yeast-like fungi: Candida albicans, Candida glabrata and mold - Aspergillus niger. It has also been shown to be effective against many viruses, including influenza (A / H1N1), polio, cytomegalovirus, smallpox, herpes zoster, HIV, hepatitis A, B, E, rubella, adenoviruses, herpes (HSV), mumps, enteroviruses, rhinoviruses, astroviruses or coronaviruses (also those responsible for development severe acute respiratory syndrome (SARS) [5].

* the antibacterial activity of the complex was assessed in relation to the bacteria present on the surface, the time of contact of the bacteria with the complex 5 min, temperature 20o C.



The antiviral mechanism of action of silver nanoparticles is complex, involves different gripping points, and is highly dependent on the type of virus. Silver nanoparticles of varying sizes (1-100 nm) have been used in in vitro studies to date, and particle size has also been found to play a significant role in silver p / viral activity. The use of smaller molecules has been shown to allow binding within the viral genome (DNA or RNA). However, silver nanoparticles can penetrate into both host and virus cells, thereby limiting the replication process. One potential gripping point is interaction with viral glycoproteins (e.g. HIV-1) or DNA (e.g. HBV). However, numerous studies have shown that silver nanoparticles can also prevent the process of virus adsorption to the surface of host cells (e.g. HSV-1, RSV, influenza), which is a key stage in the development of infection [7].



Application in the gynecology of the TIAB silver complex

Vaginal inflammation is one of the most common gynecological diseases. Recurrent intimate infections can occur in women of all ages. They may be a consequence of antibiotic therapy, which leads to disorders of the vaginal microbiome and excessive development of pathogenic organisms. The etiology of these infections is diverse, but they may have a bacterial and fungal (yeast vaginosis) basis. The direct cause of the disease and inflammation can be both the excessive expansion of aerobic bacteria (e.g. Streptococcus agalactiae, Escherichia coli and Enterococcus spp.) And anaerobic (Bacteroides spp., Fusobacterium spp., Prevotella spp., Gardnerella vaginalis, Mobiluncus spp. .). However, inflammation can also be a symptom of sexually transmitted infections (e.g. Trichomonas vaginalis, Neisseria gonorrhoeae or Chlamydia trachomatis), as well as with vaginal fungal infection (candidiasis). In some cases, it will be sufficient to use a suitable probiotic or agent to maintain the acidic environment of the vagina. However, sometimes more intensive treatment with anti-bacterial or anti-fungal substances is necessary. However, it is more and more often found that the resistance of microorganisms causing vaginal infections to commonly used antibiotics is increasing. Also some strains of yeast (C. glabrata) are naturally resistant to substances from the imidazole group, commonly used to treat this type of infection [5].

Given the difficulty in establishing the etiological factor of vaginal inflammation, topical application of antiseptic substances may be helpful. These preparations can be helpful not only in fighting infection, but also in restoring the balance of the vaginal microbiome caused by antibiotic therapy. One option is to use topical preparations containing silver compounds. However, in the case of colloidal silver, unfavorable aggregation may occur, which limits its biological activity and may contribute to the development of resistance. This problem has been eliminated by using the TIAB complex, thanks to which it is possible to obtain a high concentration of Ag + ions. In addition, after using the TIAB complex, it is possible to achieve a synergistic effect of silver ions and benzalkonium chloride, which significantly increases the effectiveness of therapy. The TIAB complex is also characterized by high activity against bacterial spores, fungi (Candida albicans, Candida glabrata and Aspergillus niger) as well as papilloma virus and HPV-2. In clinical studies, it was found that the TIAB silver complex may be an alternative treatment for vaginal and vulvar infections (of bacterial and viral etiology), as well as for preventing the recurrence of genital herpes caused by HSV-2. Thus, it can be concluded that topical application of TIAB silver complexes is an effective method of combating vaginal infections of various etiologies. At the same time, it reduces the use of antibiotics, and thus reduces the risk of intestinal microbiome disorders and drug resistance [5].

Preparations containing the TIAB silver complex may also be recommended for patients with an abnormal low-grade cytological test or a low-grade ASC-US and L-SIL lesion. The results of clinical studies confirmed that the use of TIAB silver in the form of a local vaginal preparation allows the prevention of the development and recurrence of bacterial, fungal and viral infections, including HSV-2. As a result of the TIAB silver therapy used, a reduction of changes in squamous epithelial cells was found in patients with primary infection with HPV human papillomavirus. The preparation has been shown to be effective in the treatment of inflammation and abnormal cytological smears. It was also found that the TIAB silver complex has protective properties and allows faster tissue regeneration in patients after cervical electroconization [8, 9].

One of the latest studies also showed that TIAB silver preparations can accelerate the healing process and regeneration of tissues in the vulva, vagina and anus, after surgery for condylomata removal using a CO2 laser. 26 patients aged 23 to 41 participated in the study. After the laser treatment, a local TIAB silver spray preparation was used. It was also recommended to continue treatment for another 10-14 days using a gel and vaginal capsules. There were no infections or redness during the treatment, and the healing process was normal. The preparations were also very tolerated because there were no signs of skin or mucous membrane irritation. Preliminary results of the conducted study allow to state that TIAB silver preparations can also be recommended for patients after surgery for condylomata acne by laser therapy. Local application of this type of products allows for simultaneous reduction of infection in healing lesions [10].



The use of the TIAB silver complex in the treatment of chronic wounds

Despite the wide availability of numerous antimicrobial products and medical devices supporting the healing process, wound healing is still a challenge for modern medicine. Wounds that are difficult to heal and are infected are particularly important. Chronic, non-treatable wounds cause pain and significantly reduce the quality of life of patients. They can also cause a generalized infection of the body. Therefore, in the course of treatment, it is important to use appropriate agents that will allow the wound to be cleaned, to eliminate microbes, and to provide an adequate environment to support the healing process [11].

The use of antiseptic products is recommended both in the prevention of infections and the prevention of their recurrence in patients at risk, as well as in the treatment of infected wounds. Currently on the market there are a number of preparations containing numerous substances with antiseptic effect. They are characterized by different antimicrobial activity and tissue tolerance, because some of them may adversely affect the healing process [11].

Preparations containing silver compounds are commonly used in the treatment of difficult to heal wounds covered by the infection process, among others burns, pressure sores or ulcers. They are most often used in the form of solutions, creams and active dressings. It is worth noting that silver ions are characterized by a wide spectrum of activity covering both bacteria and fungi, which is particularly beneficial in the treatment of infections of mixed etiology. The range of preparations recommended for wound care also includes spray and gel products containing the TIAB silver complex. Despite the low content of silver, these preparations are characterized by a wide antimicrobial spectrum, while ensuring a high level of safety of use. In clinical trials, it was also shown that preparations containing the TIAB complex reduce itching, redness and swelling, and thus accelerate the healing process, eliminate the inflammatory process and alleviate pain. The local action of the complex creates an antibacterial barrier on the wound surface, enabling the creation of the best microenvironment for tissue regeneration, while reducing the risk of recurrence of infection. The effectiveness of preparations containing the TIAB silver complex has been confirmed in patients with ulcers and pressure sores, where significant acceleration of the epithelization process and reduction of the wound surface have been demonstrated [12].

TIAB silver complex in the prevention of infections and reduction of bacterial biofilm

Due to the gradually increasing resistance to antimicrobial substances, prevention of infections through the use of appropriate antiseptic preparations is of increasing importance. Particular attention is paid to patients with pressure sores or burns, but potential infections of postoperative wounds are an equally important problem. An infection within a wound can lead to a delay in the healing process, and in the event of improper handling, can cause a generalized infection of the body, and thus lead to serious clinical consequences, e.g. sepsis. It is worth noting that a number of microorganisms, whose presence is found within chronic wounds, also have the ability to create biofilm structures, which further hinders the healing process and significantly increases the cost of treatment. Biofilm protects microorganisms against environmental conditions, the host's immune system, and also limits the penetration of antibiotics and antiseptics. Therefore, the key element of infection prevention is proper postoperative wound care, reduction of infection risk and prevention of bacterial biofilm formation [13].

The study by Puca et al. Evaluated the activity of TIAB silver complexes in reducing the formation of bacterial biofilm structure. Antibacterial activity was evaluated in vitro against Staphylococcus aureus, Enterococcus faecalis and E. coli, whose presence is most commonly found in postoperative wounds. Minimal inhibitory concentration (MIC) and minimal biofilm inhibitory concentrations (MBIC) were determined. Antimicrobial and antibacterial activity has been demonstrated for S. aureus and E. faecalis, but lower efficacy against E. coli. Based on the results of this study, it can be concluded that the use of TIAB silver complexes has the potential to reduce the risk of surgical site infections and limit biofilm formation [14].

It has also been shown that the TIAB silver complex can be an effective element in the prevention of infections after non-surgical periodontological treatment. The preparation was applied locally within the oral cavity in patients undergoing scalping and root smoothing. Subgingival plaque samples were taken for microbiological evaluation. A significant reduction in the number of microorganisms was found, which confirms that the local application of the TIAB silver complex may be an element supporting the treatment of chronic periodontitis after dental procedures [15].

Considering the use of the TIAB silver complex in dentistry, it is also worth paying attention to the study conducted by Besinis et al. Where its antibacterial effectiveness was compared with the activity of chlorhexidine - a substance that is commonly used in mouthwashes. The TIAB silver complex was characterized by almost 25 times higher antimicrobial efficacy [16].



Summary

The TIAB silver complex is a patented combination based on Ag + silver ions covalently bonded to the titanium molecule to which benzalkonium chloride is attached. This combination ensures high antimicrobial effectiveness and limits the conversion of Ag + ions to the inactive, metallic Ag0 form. This form increases the durability of silver ions, and also limits the possibility of accumulation of the Ag0 form in tissues, which ensures local action, high tolerance, safety and no irritating effect. In addition, the use of silver nanoparticles allowed to obtain a form with high anti-bacterial and anti-fungal efficacy. In addition, silver nanoparticles show activity against viruses, including influenza, smallpox, shingles, HIV, HBV, herpes and coronaviruses responsible for the development of severe acute respiratory distress syndrome (SARS).

Currently, the TIAB complex is one of the active ingredients in medical devices commonly used in dermatology, surgery or gynecology. It is available in a wide range of preparations, including in the form of a dry spray or cream (Argotiab®) and is after Argosulfan (silver sulfadiazine) the most commonly used form of active silver. These preparations are dedicated not only to treat difficult to heal wounds such as burns, pressure sores or ulcers, but also skin lesions or minor abrasions. They provide optimal conditions within the wound and thus accelerate the epithelization process. In addition, they form a protective barrier, prevent wound maceration, while demonstrating a broad spectrum of antimicrobial activity. In gynecology, the TIAB silver complex is used in the form of gel and vaginal capsules (Hexatiab®). They have protective properties, prevent the development and recurrence of bacterial, fungal and viral infections, including HSV-2.

At the same time, these products support the process of treating lesions of the intimate area, soothe irritation, burning and itching. The use of TIAB silver complexes allows for effective, topical antimicrobial treatment, and thus reduces the occurrence of adverse effects associated with systemic antibiotic therapy. An important indication for the TIAB silver cream complex (Argotiab®) is the formation of an antibacterial barrier on the skin at central puncture sites in hospitalized and dialyzed patients. Another potential application of the TIAB complex should be indicated, e.g. in the production of substances for surface use, used for multiple spraying of walls in public spaces or in the production of hospital beds, thus obtaining a type of surface with antimicrobial properties. The surfaces prepared in this way should be protected against adhesion and development of bacteria and fungi. However, such use of the TIAB complex requires further research.



Dr. n. Farm Piotr Szoka - Medical University of Bialystok, Department of Pharmacology

Dr. n. Farm Paweł Lisiecki - Medical University of Lodz, Department of Pharmaceutical Microbiology and Microbiological Diagnostics